Quinone methide adducts

FIGURE 9.2 Time-dependent evolution of quinone methide adducts formed by an equimolar mixture of dA, dC, dG, and dT was monitored by reverse-phase chromatography. Source Reproduced with permission from Chem. Res. Toxicol. 2005, 18, 1364-1370.48 Copyright 2005, American Chemical Society. 

TABLE 9.1 Substituents Affect the Lability of Quinone Methide Adducts... 

Angle, S. R. Yang, W. pH-Dependent stability and reactivity of a thiol-quinone methide adduct. Tetrahedron Lett. 1992, 33, 6089-6092. 

For the p-meLhoxybenzyl cation the equilibrium constant for reaction with the sulfur nucleophile is more favorable than that for the chloride ion by a factor of 107. As already discussed on p. 73 (cf. Table 6) this is a normal reflection of the greater carbon basicity of sulfur than chlorine. However in the case of the quinone methide the relative magnitudes of the equilibrium constants is reversed, with Me2s/ ci = 0.008. Toteva and Richard attribute this to the unfavorable steric and electrostatic interactions between the CF3 groups of the quinone methide adduct and the positively charged sulfonium ion. 

DNA alkylation has the potential to yield a time-dependent spectrum of adducts, in which initially formed kinetically favored lesions give way to the thermodynamically favored adducts over time. Reversible alkylation has been observed at several of the nucleophilic sites in DNA, including N3A (CC-1065,7, Scheme 8.10, duocarmycin, 8)," " NIA (qui-none methide, 9)," N7G (leinamycin, Schane 8.11, aflatoxin Bj epoxide, 10 and quinone methide, 9),57.ii4.ii8 (quinone methide, 9)," and bPG (ecteinascidin 743,11)." The bidentate Nl/ISPG adduct of malondialdehyde also forms reversibly. ... 

Weinert, E. E. Dondi, R. Colloredo-Melz, S. Frankenheld, K. N. Mitchell, C. H. Freccero, M. Rokita, S. E. Substituents on quinone methides strongly modulate formation and stability of their nucleophilic adducts. J. Am. Chem. Soc. 2006, 128, 11940-11947. 

The prototype o-quinone methide (o-QM) and / -quinone methide (p-QM) are reactive intermediates. In fact, they have only been detected spectroscopically at low temperatures (10 K) in an argon matrix,1 or as a transient species by laser flash photolysis.2 Such a reactivity is mainly due to their electrophilic nature, which is remarkable in comparison to that of other neutral electrophiles. In fact, QMs are excellent Michael acceptors, and nucleophiles add very fast under mild conditions at the QM exocyclic methylene group to form benzylic adducts, according to Scheme 2.1.2a 3... 

K. Mizutani, T. Electronic and structural requirements for metabolic activation of butylated hydroxytoluene analogs to their quinone methides, intermediates responsible for lung toxicity in mice. Biol. Pharm. Bull. 1997, 20, 571-573. (c) McCracken, P. G. Bolton, J. L. Thatcher, G. R. J. Covalent modification of proteins and peptides by the quinone methide from 2-rm-butyl-4,6-dimethylphenol selectivity and reactivity with respect to competitive hydration. J. Org. Chem. 1997, 62, 1820-1825. (d) Reed, M. Thompson, D. C. Immunochemical visualization and identification of rat liver proteins adducted by 2,6-di- m-butyl-4-methylphenol (BHT). Chem. Res. Toxicol. 1997, 10, 1109-1117. (e) Lewis, M. A. Yoerg, D. G. Bolton, J. L. Thompson, J. Alkylation of 2 -deoxynucleosides and DNA by quinone methides derived from 2,6-di- m-butyl-4-methylphenol. Chem. Res. Toxicol. 1996, 9, 1368-1374. 

Many of the contributors to this volume have addressed the reactions of quinone methides with DNA nucleophiles. The 13C-labeled methide center has the potential of identifying the type and number of such adducts using 13C-NMR. An obvious... 

To assess the trapping of biological nucleophiles, the pyrido[l,2-a]indole cyclopropyl quinone methide was generated in the presence of 5 -dGMP. The reaction afforded a mixture of phosphate adducts that could not be separated by reverse-phase chromatography (Fig. 7.16). The 13C-NMR spectrum of the purified mixture shown in Fig. 7.16 reveals that the pyrido [1,2-a] indole was the major product with trace amounts of azepino[l,2-a] indole present. Since the stereoelec-tronic effect favors either product, steric effects must dictate nucleophilic attack at the least hindered cyclopropane carbon to afford the pyrido[l,2-a]indole product. Both adducts were stable with elimination and aromatization not observed. In fact, the pyrido [1,2-a] indole precursor (structure shown in Scheme 7.14) to the pyrido [l,2-a]indole cyclopropyl quinone methide possesses cytotoxic and cytostatic properties not observed with the pyrrolo [1,2-a] indole precursor.47... 

Quinone Methide Regeneration is Required for Isomerization between Its N1 and 6-Amino Adducts of dA... 

Kinetic and Thermodynamic Adducts Formed by Quinone Methides... 

SCHEME 9.22 Intramolecular trapping produces a self-adduct of the quinone methide conjugate. 

SCHEME 9.24 A quinone methide conjugate for cross-linking DNA through recognition of the minor groove primarily formed self-adducts irreversibly. 

Lemercier, J.-N. Meier, B. Gomez, J. D. Thompson, J. A. Inhibition of glutathione S-transferase Pl-1 in mouse lung epithelial cells by the tumor promoted 2,6,di-tert-butyl-4-methylene-2,5-cylcohexadienone (BHT-quinone methide) protein adducts investigated by electrospray mass spectrometry. Chem. Res. Toxicol. 2004, 17, 1675-1683. 

Marques, M. M. Beland, F. A. Identification of tamoxifen-DNA adducts formed by 4-hydroxytamoxifen quinone methide. Carcinogenesis 1997, 18, 1949-1954. 

Acolbifene is also metabolized to a QM (Scheme 10.10)64 formed by oxidation at the C-17 methyl group. This QM is considerably more reactive compared to the tamoxifen quinone methide, which indicates that the acolbifene quinone methide is an electrophile of intermediate stability (Table 10.2). In addition, the acolbifene QM was determined to react with deoxynucleosides, with one of the major adducts resulting from reaction with the exocyclic amino group of adenine.64... 

Bolton, J. L. Le Blanc, J. C. Y. Siu, K. W. M. Reaction of quinone methides with proteins analysis of myoglobin adduct formation by electrospray mass spectrometry. Biol. Mass... 

Bodell, W. J. Ye, Q. Pathak, D. N. Pongracz, K. Oxidation of eugenol to form DNA adducts and 8-hydroxy-2 -deoxyguanosine role of quinone methide derivative in DNA adduct formation. Carcinogenesis 1998, 19, 437 143. 

Cleavage of 8-0-4-ethers in alkaline pulping is also facilitated by HS as used in kraft pulping.98 The major mechanisms (Fig. 12.8b) are via addition to the quinone methide QM1 to give adduct 19, followed by anchimerically assisted fragmentation via a thioepoxide 20. 

Landucci, L. L. Ralph, J. Adducts of anthrahydroquinone and anthranol with lignin model quinone methides. 1. Synthesis and characterization. J. Org. Chem. 1982, 47, 3486-3495. 

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